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Interactions Between Nuclei and the Cytoskeleton Are Mediated by SUN-KASH Nuclear-Envelope Bridges

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Interactions Between Nuclei and the Cytoskeleton Are Mediated by SUN-KASH Nuclear-Envelope Bridges CB26CH17-Starr ARI 3 September 2010 19:43 Interactions Between Nuclei and the Cytoskeleton Are Mediated by SUN-KASH Nuclear-Envelope Bridges Daniel A. Starr and Heidi N. Fridolfsson Department of Molecular and Cellular Biology, University of California, Davis, California 95616; email: [email protected], [email protected] Annu. Rev. Cell Dev. Biol. 2010. 26:421–44 Key Words First published online as a Review in Advance on nuclear positioning, outer nuclear membrane, laminopathies, May 27, 2010 microtubule motor targeting, Syne, Nesprin The Annual Review of Cell and Developmental Biology is online at cellbio.annualreviews.org Abstract This article’s doi: The nuclear envelope links the cytoskeleton to structural components 10.1146/annurev-cellbio-100109-104037 of the nucleus. It functions to coordinate nuclear migration and anchor- Copyright c 2010 by Annual Reviews. age, organize chromatin, and aid meiotic chromosome pairing. Forces All rights reserved by University of California - Davis on 10/14/10. For personal use only. generated by the cytoskeleton are transferred across the nuclear enve- 1081-0706/10/1110-0421$20.00 lope to the nuclear lamina through a nuclear-envelope bridge consist- ing of SUN (Sad1 and UNC-84) and KASH (Klarsicht, ANC-1 and Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org Syne/Nesprin homology) proteins. Some KASH-SUN combinations connect microtubules, centrosomes, actin filaments, or intermediate fil- aments to the surface of the nucleus. Other combinations are used in cell cycle control, nuclear import, or apoptosis. Interactions between the cy- toskeleton and the nucleus also affect global cytoskeleton organization. SUN and KASH proteins were identified through genetic screens for mispositioned nuclei in model organisms. Knockouts of SUN or KASH proteins disrupt neurological and muscular development in mice. De- fects in SUN and KASH proteins have been linked to human dis- eases including muscular dystrophy, ataxia, progeria, lissencephaly, and cancer. 421 CB26CH17-Starr ARI 3 September 2010 19:43 Contents Attachment of Nuclei to INTRODUCTION................. 422 Intermediate Filaments . 430 DISCOVERY OF KASH KASH AND SUN PROTEINS AND SUN PROTEINS AND REGULATE THE GLOBAL THE FORMATION OF THE CYTOSKELETON . 431 NUCLEAR-ENVELOPE FUNCTIONS OF KASH-SUN BRIDGE........................ 423 BRIDGES IN MEIOTIC Discovery of SUN Proteins . 423 CHROMOSOME SUN Proteins Constitute the MOVEMENTS. 431 Inner Nuclear Membrane Half OTHER FUNCTIONS OF KASH of the Nuclear-Envelope ANDSUNPROTEINS.......... 432 Bridge . 423 C. elegans KDP-1 Regulates the Discovery of KASH Proteins. 425 Progression of the Cell Cycle . 432 KASH Proteins Interact WIPs Recruit RanGAP with SUN Proteins to Complete to the Outer Nuclear the Nuclear-Envelope Bridge . 427 Membrane.................... 433 FUNCTIONS OF KASH Recruitment of CED-4 to the PROTEINS AT THE OUTER Nuclear Envelope to Mediate NUCLEAR MEMBRANE IN Apoptosis . 433 POSITIONING NUCLEI . 428 FUNCTIONS OF KASH-SUN Anchoring Nuclei to the Actin PROTEINS IN MAMMALS: Cytoskeleton.................. 428 MOUSE MODELS AND Centrosome Attachment to the HUMANDISEASES............ 433 Nuclear Envelope during Nuclear Positioning in Muscles PronuclearMigration.......... 428 and Muscular Dystrophies . 433 Nuclear Anchorage to Neuronal Functions of Microtubules through Dynein. 429 SUN-KASH Proteins . 435 Targeting and Coordination of SUN-KASH Proteins in Aging. 436 Kinesin-1 and Dynein at the SUN-KASH Proteins in Skin NuclearSurface............... 430 Development, Ciliogenesis, andCancer.................... 436 by University of California - Davis on 10/14/10. For personal use only. Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org INTRODUCTION the nucleus interacts with the cytoskeleton, how The nuclear envelope is a specialized exten- forces are transferred across the nuclear enve- sion of the endoplasmic reticulum (ER) that lope, and how these processes relate to human compartmentalizes the genome. It also pro- disease. vides physical rigidity to the nucleus, organizes The nuclear envelope consists of two par- chromatin, functions in meiotic chromosome allel membranes, the inner nuclear mem- ER: endoplasmic pairing, and positions the nucleus within the brane (INM) and outer nuclear membrane reticulum cell. Interactions between the cytoskeleton and (ONM), that are contiguous at the nuclear pore INM: inner nuclear the nuclear envelope are central to all of these (Figure 1a). The ONM is also contiguous membrane functions. The same molecular mechanisms are with the ER (reviewed in Franke et al. 1981). ONM: outer nuclear used in these processes to transfer forces gener- The membranes of the nuclear envelope are membrane ated in the cytoskeleton to the structural com- supported by the nuclear lamina that imme- ponents inside the nucleus. Here we review how diately underlies the INM. In metazoans, the 422 Starr · Fridolfsson CB26CH17-Starr ARI 3 September 2010 19:43 lamina consists of membrane proteins, the ab intermediate filament lamin, and proteins as- ER sociated with chromatin (reviewed in Gruen- baum et al. 2005). To form a nuclear-envelope bridge, membrane proteins are trafficked from the ER membrane either to the INM to interact SUN KASH with the lamina, or to the ONM to interact with protein protein the cytoskeleton. To complete the bridge, INM and ONM proteins interact with each other in the perinuclear space. The current KASH- NPC SUN nuclear-envelope bridging model, also re- ferred to as the linker of nucleoskeleton and cy- toskeleton (LINC) complex model, posits that SUN (Sad1 and UNC-84) proteins in the INM INM ONM interact with KASH (Klarsicht, ANC-1, and Syne/Nesprin homology) proteins of the ONM Cytoplasm to span the nuclear envelope (Figure 1b). Nucleus DISCOVERY OF KASH AND SUN PROTEINS AND 0.2 μm THE FORMATION OF THE Figure 1 NUCLEAR-ENVELOPE BRIDGE Klarsicht, ANC-1, and Syne/Nesprin homology (KASH) and Sad1 and UNC-84 (SUN) proteins bridge the two membranes of the nuclear envelope. Discovery of SUN Proteins (a) A transmission electron microscopy (TEM) image and (b) a schematic representation of the nuclear envelope in an amphibian oocyte showing how Our current understanding of the molecu- the inner nuclear membrane (INM), outer nuclear membrane (ONM), and lar mechanisms of the SUN-KASH nuclear- endoplasmic reticulum (ER) are contiguous. NPC, nuclear pore complex. A envelope bridge is based on characterizations generic SUN and KASH protein bridge is drawn with conserved SUN (red ) of genetic mutants in Caenorhabditis elegans and KASH (purple) domains in the perinuclear space of the nuclear envelope. TEM image reproduced with permission from J. Cell Biol. (Franke et al. 1981). and Drosophila with mispositioned nuclei (re- viewed in Starr & Fischer 2005, Starr & Han termed the SUN domain (Malone et al. 1999). 2005, Wilhelmsen et al. 2006). SUN proteins Sad1 is an essential component of the spindle were discovered by molecular analysis of C. pole body required for normal spindle archi- elegans unc-84. Alleles of unc-84 were orig- by University of California - Davis on 10/14/10. For personal use only. tecture (Hagan & Yanmagida 1995). Overex- inally isolated because of their defects in P pressed Sad1::green fluorescent protein (GFP) cell nuclear migration, which results in miss- accumulates at the nuclear envelope, suggest- Annu. Rev. Cell Dev. Biol. 2010.26:421-444. Downloaded from www.annualreviews.org ing neurons and vulval cells, leading to unco- ing an additional role for Sad1 in nuclear posi- ordinated and egg-laying defective phenotypes tioning during interphase (Goshima et al. 1999, Nuclear-envelope (Figure 2a, Horvitz & Sulston 1980, Sulston bridge: a complex of Tran et al. 2001). UNC-84 also localizes to the & Horvitz 1981). unc-84 alleles also cause nu- SUN proteins at the nuclear envelope (Lee et al. 2002, Malone et al. clear migration defects in epidermal precursors INM and KASH 1999). Proteins with SUN domains are referred proteins at the ONM (Figure 2b, Horvitz & Sulston 1980, Sulston to as SUN proteins and localize to the INM. that transfer forces & Horvitz 1981). The molecular cloning of generated in the UNC-84 (Malone et al. 1999) in effect founded cytoplasm to the the SUN-KASH field. SUN Proteins Constitute the nuclear lamina The C terminus of UNC-84 was found to Inner Nuclear Membrane Half LINC: linker of be conserved with the C termini of Schizosac- of the Nuclear-Envelope Bridge nucleoskeleton and charomyces pombe Sad1 and two human pro- SUN proteins are conserved across eukary- cytoskeleton teins; each contains a ∼175 amino acid domain otes including fungi, plants, animals, and basal www.annualreviews.org • Nuclear-Cytoskeletal Interactions 423 CB26CH17-Starr ARI 3 September 2010 19:43 a P cell nuclear migration in C. elegans larvae b Nuclear migration in C. elegans embryo Wild type Wild type Ventral cord Forms vulva and neurons unc-83 or unc-84 unc-83 or unc-84 Egl and Unc Dorsal cord animals c Nuclear migration in Drosophila eye disc d Nuclear achorage in C. elegans syncytia Wild type klarsicht or klaroid Wild type Apical anc-1 or unc-84 Basal Figure 2 Genetic models for studying nuclear positioning. (a) Nuclear migration in hypodermal P cells during the first larval stage of Caenorhabditis elegans. Nuclei (dark blue) migrate from a lateral to a ventral position through the cytoplasm (light blue). P cells normally go on to form the vulva and neurons in the ventral cord. Mutations in unc-83 or unc-84 disrupt nuclear migration and the P cells die, resulting in egg-laying defective (Egl) and uncoordinated (Unc) animals. (b) Nuclear migration in C. elegans embryonic hypodermal cells. Right (light blue)andleft(light green) hyp7 precursors align along the dorsal cord of a pre-elongation embryo (brown circle, dorsal view, anterior to the left) and intercalate to form a row of column-shaped cells spanning the dorsal midline. Nuclei (dark blue and dark green) then migrate the length of the cell from right to left (blue) or left to right (green). Mutations in unc-83 and unc-84 disrupt nuclear migration, and all nuclei end up in the dorsal cord instead of their normal, lateral positions.
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